Cervical cancer is the third most common cancer in women in the world, responsible for close to 300,000 deaths annually. The cervical cancer burden is particularly severe in sub-Saharan Africa due to the absence of population-wide screening programs and a high prevalence of HIV infection. Cervical cancer is caused by infection and persistence of oncogenic alpha-clade human papillomaviruses (HPV). Oncogenic HPV types 16, 18, 31, 33, 35, 45, 52, and 58 account for approximately 92% of cervical cancer worldwide;HPV16 and HPV18 account for the largest proportion in Africa (48% and 23%, respectively) as in the rest of the world. Research over the past two decades shows that for a given HPV type, intratypic sequence variations of the HPV genome (defined as lineage and sublineages) resulting from long-term viral evolution influence the pathogenic effects of this virus family in model systems, including effects on expression of HPV oncogenes, interaction of oncogenes with cellular factors, and antigenicity. And, most studies find that the certain HPV16 lineages are associated with higher risks of persistence, pre-cancer, and cancer. Several studies hint that a patient's HIV status might influence which HPV lineage causes her cervical cancer, and that HPV sequence may influence survival. Whether HPV lineages and/or sublineages influence the burden of cervical cancer in sub-Saharan Africa is unknown. Only three studies totaling <90 cases have sequenced HPV genomes (all HPV16) in cervical cancer specimens from this region, but have not examined whether the distribution of variants is influenced by HIV status or is associated with survival. In a population of 300 first, primary, invasive cervical carcinomas diagnosed in Ugandan women, we will: 1) determine HPV types using reverse line-blot arrays, and lineages and sublineages by PCR-based direct sequencing of the LCR/E6/E7 region followed by phylogenetic analyses;2) assess associations between HPV variation and tumor and patient characteristics such as histology, stage, and HIV status;and 3) determine the association between HPV types, lineages, and sublineages and cervical cancer survival. This study will provide unique information about variation in the HPV genome and its contribution to the cervical cancer epidemic in Uganda.

Public Health Relevance

Invasive cervical cancer is the third-most common cancer in women in the world, and occurs at epidemic proportions in sub-Saharan Africa. Human papillomavirus (HPV) causes cervical cancer, and this project will determine whether variation in the HPV DNA sequence plays a role in this public health problem.